Prescription Amphetamines Boost Risk for New Psychosis or Mania
A recent study seeks to guide prescribers on dose levels and other factors that affect the rare but serious risk of first-time psychosis or incident mania with psychostimulants.
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Young adults taking prescription amphetamines were nearly three times more likely to develop first-episode psychosis or incident mania than those taking methylphenidate, according to a study issued by AJP.
The Food and Drug Administration added warnings to prescription stimulant labels in 2007 after studies showed they increased risk of psychosis or mania, even among patients with no prior history of these symptoms. Despite a more than five-fold increase in amphetamine prescribing rates in the past two decades, “there are currently no published studies to guide prescribers on dose levels and other factors that impact the rare but serious risk,” wrote Lauren V. Moran, M.D., M.P.H., of McLean Hospital in Belmont, Massachusetts, and colleagues.
The Most Important Modifiable Factor
Moran and colleagues analyzed health records for first-time inpatients ages 16 to 35 at McLean Hospital between 2005 and 2019. They matched 1,374 individuals who were admitted for new-onset psychosis or mania with 2,748 admitted with other diagnoses. After accounting for other substance use, patient psychiatric history, and other variables, they found:
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Patients taking any dose of prescription amphetamines in the past month were 2.68 times more likely to develop psychosis or mania than patients not taking these medications; patients taking high-dose amphetamines (>30 mg dextroamphetamine or equivalent) were 5.3 times more likely to develop psychosis or mania.
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Patients age 23 or older had higher odds of psychosis or mania than younger patients, possibly due to the higher average amphetamine dose researchers observed in the older group.
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Patients taking prescription amphetamines were 2.85 times more likely to develop psychosis or mania than those taking methylphenidate. Those taking methylphenidate did not have increased odds of psychosis or mania than those not taking these medications.
“Our results suggest that prescription amphetamine dose is the most important modifiable factor associated with stimulant-related psychosis or mania…. Our findings suggest that clinicians can mitigate the risk of psychosis or mania by avoiding doses above 30 mg dextroamphetamine equivalents,” Moran and colleagues wrote. “In patients who experience impairment from ADHD symptoms who may benefit from doses above 30 mg dextroamphetamine equivalents, careful monitoring with screening for symptoms of psychosis or mania is critically warranted.
Ryan S. Sultan, M.D., said that he prefers to start with nonstimulant options such as bupropion or atomoxetine when treating a new patient with attention-deficit/hyperactivity disorder. Although amphetamine products tend to be more effective, they also carry greater risks.
“This is of particular importance given that psychosis and mania are often associated with lack of insight,” the researchers continued. “Symptoms that develop in the context of prescription amphetamine use could emerge without the patient’s awareness, leading to a delay in detection.”
Diagnosis, Lifestyle Modification
An increasing number of people are presenting at psychiatrists’ offices saying they have ADHD, Ryan S. Sultan, M.D., assistant professor of clinical psychiatry and principal investigator for the Sultan Lab for Mental Health Informatics at Columbia University, told Psychiatric News. Often, the true culprit is depression, anxiety, or even unrealistic expectations for the number of hours an individual can focus on their work.
“Don’t let patients tell you their diagnosis. Evaluate their condition on your own,” Sultan said. “… There is a laundry list of conditions that involve attention and memory problems, and ADHD is not even the most common one.”
Psychostimulants are generally safe, but as prescription of these medications has increased, particularly during the pandemic, and as older patients are exposed to them, their risks are becoming more evident, Sultan said. He added that some individuals live “closer to the line” of psychosis or mania, due to factors such as their genetic background. Stress, sleep deprivation, and trauma also typically play a role among those who develop stimulant-induced psychosis or mania.
It is well established that excess dopamine plays a role in the development of psychosis and mania, and while all psychostimulants increase dopamine, amphetamines are among the most powerful because they both block dopamine reuptake and trigger the release of stored dopamine in neurotransmitters. “So, it makes sense that in high doses, amphetamines could bump some patients over that line into psychotic-like experiences,” Sultan said.
Sultan said he avoids starting a new patient with ADHD on an amphetamine product as a first-line treatment because it is more likely to produce euphoria. “If you start with an amphetamine product, you’re going to have a lot of trouble getting the patient to accept anything else.”
While amphetamine products tend to be more effective, they also carry greater risks. In addition to psychosis/mania, amphetamines pose greater risks of dependence, abuse/misuse, and cardiovascular side effects such as high blood pressure than do methylphenidate or nonstimulant options. Sultan typically starts with the latter, such as bupropion or atomoxetine, which can be combined with other medications if needed. Failing those, Sultan then prescribes a methylphenidate product.
Although pharmacotherapy is highly effective for ADHD, with an 80% to 90% response rate, Sultan said that multiprong approaches involving lifestyle modifications work best, such as the adoption of a set routine, to-do list, schedule, calendar, and a place to write down important items. Vigorous exercise is also a good way for patients to boost dopamine and improve ADHD symptoms.
“If we do all three—medication, lifestyle modification, and vigorous exercise—we can probably get away with a lower dose of the meds,” Sultan said.
This study was supported by a grant from the National Institute of Mental Health. ■
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Published in print: December 1, 2024 – December 31, 2024
Published online: 2 December 2024
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